title: Mitochondrial abnormality associates with type-specific neuronal loss and cell morphology changes in the pedunculopontine nucleus in Parkinson disease.
abstract: Cholinergic neuronal loss in the pedunculopontine nucleus (PPN) associates with abnormal functions, including certain motor and nonmotor symptoms. This realization has led to low-frequency stimulation of the PPN for treating patients with Parkinson disease (PD) who are refractory to other treatment modalities. However, the molecular mechanisms underlying PPN neuronal loss and the therapeutic substrate for the clinical benefits following PPN stimulation remain poorly characterized, hampering progress toward designing more efficient therapies aimed at restoring the PPN's normal functions during progressive parkinsonism. Here, we investigated postmortem pathological changes in the PPN of PD cases. Our study detected a loss of neurons producing gamma-aminobutyric acid (GABA) as their output and glycinergic neurons, along with the pronounced loss of cholinergic neurons. These losses were accompanied by altered somatic cell size that affected the remaining neurons of all neuronal subtypes studied here. Because studies showed that mitochondrial dysfunction exists in sporadic PD and in PD animal models, we investigated whether altered mitochondrial composition exists in the PPN. A significant up-regulation of several mitochondrial proteins was seen in GABAergic and glycinergic neurons; however, cholinergic neurons indicated down-regulation of the same proteins. Our findings suggest an imbalance in the activity of key neuronal subgroups of the PPN in PD, potentially because of abnormal inhibitory activity and altered cholinergic outflow.
authors.affiliation: Centre for NeuroInflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Hammersmith, United Kingdom. Electronic address: i.pienaar@imperial.ac.uk.
authors.forename: Ilse S
authors.initials: IS
authors.lastname: Pienaar
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Centre for Human Metabolomics, Biochemistry Division, North-West University, Potchefstroom, South Africa.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Elson
authors.affiliation: Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Racca
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.
authors.forename: Glyn
authors.initials: G
authors.lastname: Nelson
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; The Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.affiliation: Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Morris
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D059329:Cholinergic Neurons / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D045042:Pedunculopontine Tegmental Nucleus / Q000378:metabolism / Q000473:pathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005680:gamma-Aminobutyric Acid